The three common isoforms of human apolipoprotein (apo) E (apoE2, apoE3, and apoE4) have remarkably different influences on plasma lipoprotein metabolism and Alzheimer's disease (AD). Genetic evidence clearly establishes that the apoE4 allele is a major risk factor for AD and that, in some populations, the apoE2 allele appears to be protective. The long-range objective of our research is to understand the role of apoE in the etiology of AD and the basis for different effects that the three isoforms have on the disease. A fundamental requirement to achieve this objective and a major focus of this proposal is to determine the basic physical-biochemical properties and structure-function relationships of the three apoE isoforms. The foundation of this proposal is based on our hypothesis that the properties and characteristics of apoE4 directly result from the interaction of the two structural domains in the protein, a phenomenon referred to as apoE4 domain interaction. The research plan is organized into three specific aims. Specific Aim l will compare the physical-biochemical properties of apoE4, apoE2, and the apoE3 homo-dimer with those of apoE3 and improve the three-dimensional structural models of apoE2, apoE3, and apoE4. Specific Aim 2 will define apoE4 domain interaction using a combination of deletion mutagenesis and x-ray crystallography. Also, a disulfide-linked model of domain interaction will be produced. Specific Aim 3 will examine the interaction of various forms of lipid-free and lipid-associated apoE with the l-28 and 1-40 Abeta peptides. These studies will provide a critical and necessary foundation for the eventual understanding of the structure-function relationships of the apoE isoforms in AD.